Constitutive KrasG12D signaling drives uncontrolled proliferation and enhances survival of cancer cells through the activation of its downstream signaling pathways, such as the MAPK and PI3K-mTOR pathways. To meet the increased anabolic needs of enhanced proliferation, cancer cells require both sufficient energy and biosynthetic precursors as cellular building blocks to fuel cell growth. Under normal conditions, differentiated cells primarily metabolize glucose through the mitochondrial tricarboxylic acid (TCA) cycle to drive the production of ATP to sustain basic cellular functions. In cancer cells, metabolic pathways are rewired in order to divert nutrients, such as glucose and glutamine, into anabolic pathways to satisfy the demand for cellular building blocks. Accumulating evidence indicates that the reprogramming of tumor metabolism is under the control of various oncogenes and oncogenic signals. The Ras oncogene in particular has been shown to promote glycolysis. However, the mechanisms by which oncogenic Kras coordinates the shift in metabolism to sustain tumor growth, particularly in the tumor microenvironment, and whether specific metabolic pathways are essential for Kras-mediated tumor maintenance remain areas of active investigation.
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers with a 5 year survival rate of 3%-5%. Malignant progression from pancreatic intraepithelial neoplasia (PanINs) to highly invasive and metastatic disease is accompanied by the early acquisition of activating mutations in the KRAS oncogene, which occurs in greater than 90% of cases, and subsequent loss of tumor suppressors including Ink4a/Arf, p53 and Smad4. Genetically engineered mouse models (GEMM) have provided genetic evidence for the role of oncogenic Kras (KrasG12D) as a major driver in PDAC initiation, with the aforementioned tumor suppressor genes constraining malignant progression. While shRNA-mediated extinction of Kras expression as well as pharmacological inhibition of its effectors can impair tumor growth in human PDAC lines, clinical trials of drugs targeting key components of the RAS-MAPK signaling pathway have shown meager responses. The paucity of clinical progress may relate to a number of factors including the lack of a tumor maintenance role for oncogenic Kras, redundancy in downstream signaling surrogates, suboptimal penetration of the drug into the tumor, and/or tumor plasticity owing to a myriad of genomic alterations and intratumoral heterogeneity. The poor response to MEK inhibitors may also relate to an insufficient understanding of the key downstream signaling surrogates of the Kras pathway in PDAC as well as what are the critical combinations to target.
Thus, what is needed in the art are reliable diagnostic methods and effective therapies for Kras-associated cancers.